Topical lfa-1 antagonists for use in localized treatment of immune related disorders

Abstract

This invention provides specifically formulated LFA-1 antagonists or pharmaceutically acceptable salts thereof that are suitable for topical delivery. In particular, the LFA-1 antagonists are particularly well suited for localized treatment by having a rapid systemic clearance rate. The invention also encompasses methods of treatment and prevention of immune related disorders using the LFA-1 topical formulations of the present invention.

1 . A pharmaceutical formulation comprising an LFA-1 antagonist or a pharmaceutically acceptable salt or ester thereof, and an excipient formulated for topical administration, wherein the LFA-1 antagonist has a systemic clearance rate greater than about 2 mL/min/kg when administered to a subject, wherein the LFA-1 antagonist comprises a compound of Formula I or II and/or its pharmaceutically acceptable salts or esters, having the following structures: 
       
         
           
           
               
               
           
         
         Wherein R 1  and R 2  are each independently hydrogen, an amino acid side chain, —(CH 2 ) m OH, —(CH 2 ) m aryl, —(CH 2 ) m heteroaryl, wherein m is 0-6, —CH(R 1A )(OR 1B ), —CH(R 1A )(NHR 1B ), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally substituted with U-T-Q, wherein U is absent, —O—, —S(O) 0-2 —, —SO 2 N(R 1A ), —N(R 1A )—, —N(R 1A )C(═O)—, —N(R 1A )C(═O)—O—, —N(R 1A )C(═O)—N(R 1B )—, —N(R 1A )—SO 2 —, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R 1A )—, —OC(═O)N(R 1A )—, —C(═N—R 1E )—, —C(═N—R 1E )—O—, —C(═N—R 1E )—N(R 1A )—, —O—C(═N—R 1E )—N(R 1A )—, —N(R 1A )C(═N—R 1E )—, —N(R 1A )C(═N—R 1E )—O—, —N(R 1A )C(═N—R 1E )—N(R 1B )—, —P(═O)(OR 1A )—O—, or —P(═O)(R 1A )—O—; 
         T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and 
         Q is hydrogen, halogen, cyano, isocyanate, —OR 1B ; —SR 1B ; —N(R 1B ) 2 , —NHC(═O)OR 1B , —NHC(═O)N(R 1B ) 2 , —NHC(═O)R 1B , —NHSO 2 R 1B , —NHSO 2 N(R 1B ) 2 , —NHSO 2 NHC(═O)OR 1B , —NHC(═O)NHSO 2 R 1B , —C(═O)NHC(═O)OR 1B , —C(═O)NHC(═O)R 1B , —C(═O)NHC(═O)N(R 1B ) 2 , —C(═O)NHSO 2 R 1B , —C(═O)NHSO 2 N(R 1B ) 2 , C(═S)N(R 1B ) 2 , —SO 2 R 1B , —SO 2 OR 1B , —SO 2 N(R 1B ) 2 , —SO 2 —NHC(═O)OR 1B , —OC(═O)—N(R 1B ) 2 , —OC(═O)R 1B , —OC(═O)NHC(═O)R 1B , —OC(═O)NHSO 2 R 1B , —OSO 2 R 1B , or an aliphatic heteroaliphatic, aryl or heteroaryl moiety, or wherein R 1  and R 2  taken together are an alicyclic or heterocyclic moiety, or together are 
       
       
         
           
           
               
               
           
         
         wherein each occurrence of R 1A  and R 1B  is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —C(═O)R 1C , or —C(═O)NR 1C R 1D ; wherein each occurrence of R 1C  and R 1D  is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R 1E  is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR 1C , —NR 1C R 1D  or —SO 2 R 1C ; 
         R 3  is —C(═O)OR 3A , —C(═O)H, —CH 2 OR 3A , —CH 2 C(═O)-alkyl, —C(═O)NH(R 3A ), —CH 2 X 0 ; wherein each occurrence of R 3A  is independently hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl heteroalkylheteroaryl moiety, or pharmaceutically acceptable salt or ester, or R 3A , taken together with R 1  and R 2 , forms a heterocyclic moiety; wherein X 0  is a halogen selected from F, Br or I; 
         wherein R 4A  and R 4B  are independently a halogen selected from F, Cl, Br or I; and R B1 , R B2  and R E  are independently hydrogen or substituted or unsubstituted lower alkyl. 
         AR 1  is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; and, 
         L is absent or is V—W—X—Y—Z, wherein each occurrence of V, W, X, Y and Z is independently absent, C═O, NR L1 , —O—, —C(R L1 )═, ═C(R L1 )—, —C(R L1 )(R L2 ), C(═N—OR L1 ), C(═NR L1 ), —N═, S(O) 0-2 ; a substituted or unsubstituted C 1-6  alkenylidene or C 2-6  alkenylidine chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO 2 —, —C(═O)C(═O)—, —C(C═O)NR L3 —, —OC(═O)—, —OC(═O)NR L3 —, —NR L3 NR L4 —, —NR L3 NR L4 C(═O)—, —NR L3 C(═O)—, NR L3 CO 2 —, NR L3 C(═O)NR L4 —, —S(═O)—, —SO 2 —, —NR L3 SO 2 —, —SO 2 NR L3 , —NR L3 SO 2 NR L4 , —O—, —S—, or —NR L3 —; wherein each occurrence of R L3  and R L4  is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl; or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and each occurrence of R L1  and R L2  is independently hydrogen, hydroxyl, protected hydroxyl, amino, protected amino, thio, protected thio, halogen, cyano, isocyanate, carboxy, carboxyalkyl, formyl, formyloxy, azido, nitro, ureido, thioureido, thiocyanato, alkoxy, aryloxy, mercapto, sulfonamido, benzamido, tosyl, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or wherein one or more occurrences of R L1  and R L2 , taken together, or taken together with one of V, W, X, Y or Z form an alicyclic or heterocyclic moiety or form an aryl or heteroaryl moiety. 
       
     
     
         2 . The formulation of  claim 1 , wherein the LFA-1 antagonist achieves a local tissue concentration of greater than about 1 μM within about 4 hours following administration to a subject. 
     
     
         3 . The formulation of  claim 2 , wherein the local tissue concentration of the LFA-1 antagonist is maintained at a concentration of greater than about 10 nM for at least about 8 hours when administered to a subject. 
     
     
         4 . The formulation of  claim 1  wherein the LFA-1 antagonist is a directly competitive antagonist. 
     
     
         5 . (canceled) 
     
     
         6 . The formulation of  claim 1 , wherein the LFA-1 antagonist has one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The formulation of  claim 6  wherein the LFA-1 antagonist is a sodium, potassium, lithium, magnesium, zinc, or calcium salt. 
     
     
         8 . The formulation of  claim 1 , wherein the LFA-1 antagonist inhibits T-cell attachment to ICAM-1 by about 50% or more at a concentration of about 100 nM. 
     
     
         9 . The formulation of  claim 1 , wherein the formulation is in the form of a gel, cream, lotion, solution, suspension, emulsion, ointment, powder, crystalline forms, spray, foam, salve, paste, plaster, paint, slow release nanoparticle, slow release microparticle, or bioadhesive. 
     
     
         10 . The formulation of  claim 1 , wherein the excipient is water, buffered aqueous solution, surfactant, volatile liquid, starch, polyol, granulating agent, microcrystalline cellulose, diluent, lubricant, acid, base, salt, emulsion, oil, wetting agent, chelating agent, antioxidant, sterile solution, complexing agent or disintegrating agent. 
     
     
         11 . The formulation of  claim 10 , wherein the surfactant is oleic acid, cetylpyridinium chloride, soya lecithin, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene-polyoxypropylene-ethylenediamine block copolymer, polyoxypropylene-polyoxyethylene block copolymer or castor oil ethoxylate. 
     
     
         12 . The formulation of  claim 1 , further comprising a topical penetration enhancer. 
     
     
         13 . The formulation of  claim 12 , wherein the topical penetration enhancer is a sulfoxide, ether, surfactant, alcohol, fatty acid, fatty acid ester, polyol, amide, terpene, alkanone or organic acid. 
     
     
         14 . The formulation of  claim 1 , further comprising at least one additional therapeutic agent. 
     
     
         15 . The formulation of  claim 14 , wherein the additional therapeutic agent is an antioxidant, antiinflammatory agent, antimicrobial agent, antiangiogenic agent, anti-apoptotic agent, vascular endothelial growth factor inhibitor, antiviral agent, calcineurin inhibitor, corticosteroid, immunomodulator, or lubricating eye drop. 
     
     
         16 . The formulation of  claim 15 , wherein the additional therapeutic agent is cyclosporine, Rebamipide, diquafasol, or lubricating eye drops. 
     
     
         17 . The formulation of  claim 1  wherein the formulation is a gel comprising about 1% W/V of a LFA-1 antagonist; up to about 15% W/V Dimethyl Isosorbide; up to about 25% W/V Transcutol; up to about 1% W/V Hydroxyethyl Cellulose; up to about 12% W/V Hexylene glycol, up to about 0.15% W/V Methylparaben; up to about 0.05% W/V Propylparaben; and water. 
     
     
         18 . The formulation of  claim 1  wherein the formulation is a ointment comprising about 1% W/V of a LFA-1 antagonist, up to about 10% W/V Dimethyl Isosorbide; up to about 0.02% W/V Butylated Hydroxytoluene; up to about 2% W/V Span 80; up to about 10% W/V White Wax; and White Petrolatum. 
     
     
         19 . The formulation of  claim 1  wherein the formulation is a water based lotion comprising about 1% W/V of a LFA-1 antagonist, up to about 15% W/V Dimethyl Isosorbide; up to about 25% W/V Transcutol; up to about 12% W/V Hexylene glycol; up to about 5% W/V Propylene Glycol; and pH 6.0 25% Trolamine, wherein the lotion is buffered to a pH of about 4.0 to about 7.5. 
     
     
         20 . The formulation of  claim 1  wherein the formulation is an aqueous solution buffered to a pH of about 6.0 to about 8.0 with Sodium Phosphate, Monobasic, comprising about 1% W/V of a LFA-1 antagonist, up to about 0.1% W/V EDTA, and, optionally, up to about 0.4% w/w Methylparaben and up to about 0.02% w/w Propylparaben. 
     
     
         21 . The formulation of  claim 1  wherein the LFA-1 antagonist is a compound having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The formulation of  claim 21  wherein the LFA-1 antagonist is any of Form A, Form B, Form C, Form D, Form E, an amorphous form, or a combination thereof of the compound of  claim 21 . 
     
     
         23 . The formulation of  claim 22  wherein the LFA-1 antagonist is form A of the compound of  claim 21 . 
     
     
         24 . A method for treatment of an inflammatory or immune related disorder in a subject comprising topically administering to said subject in need thereof a formulation comprising an LFA-1 antagonist or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable excipient, wherein the LFA-1 antagonist has a systemic clearance rate greater than about 2 mL/min/kg when administered to a subject, wherein the LFA-1 antagonist is a compound of Formula (I) or (II) and/or its pharmaceutically acceptable salts or esters, having the following structures: 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  are each independently hydrogen, an amino acid side chain, —(CH 2 ) m OH, —(CH 2 ) m aryl, —(CH 2 ) m heteroaryl, wherein m is 0-6, —CH(R 1A )(OR 1B ), —CH(R 1A )(NHR 1B ), U-T-Q, or an aliphatic, alicyclic, heteroaliphatic or heteroalicyclic moiety optionally substituted with U-T-Q, wherein U is absent, —O—, —S(O) 0-2 —, —SO 2 N(R 1A ), —N(R 1A )—, —N(R 1A )C(═O)—, —N(R 1A )C(═O)—O—, —N(R 1A )C(═O)—N(R 1B )—, —N(R 1A )—SO 2 —, —C(═O)—, —C(═O)—O—, —O—C(═O)—, aryl, heteroaryl, alkylaryl, alkylheteroaryl, —C(═O)—N(R 1A )—, —OC(═O)N(R 1A )—, —C(═N—R 1E )—, —C(═N—R 1E )—O—, —C(═N—R 1E )—N(R 1A )—, —O—C(═N—R 1E )—N(R 1A )—, —N(R 1A )C(═N—R 1E )—, —N(R 1A )C(═N—R 1E )—O—, —N(R 1A )C(═N—R 1E )—N(R 1B )—, —P(═O)(OR 1A )—O—, or —P(═O)(R 1A )—O—; 
         T is absent, an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and 
         Q is hydrogen, halogen, cyano, isocyanate, —OR 1B ; —SR 1B ; —N(R 1B ) 2 , —NHC(═O)OR 1B , —NHC(═O)N(R 1B ) 2 , —NHC(═O)R 1B , —NHSO 2 R 1B , NHSO 2 N(R 1B ) 2 , —NHSO 2 NHC(═O)OR 1B , —NHC(═O)NHSO 2 R 1B , —C(═O)NHC(═O)OR 1B , C(═O)NHC(═O)R 1B , —C(═O)NHC(═O)N(R 1B ) 2 , —C(═O)NHSO 2 R 1B , —C(═O)NHSO 2 N(R 1B ) 2 , C(═S)N(R 1B ) 2 , —SO 2 R 1B , —SO 2 OR 1B , —SO 2 N(R 1B ) 2 , —SO 2 —NHC(═O)OR 1B , —OC(═O)—N(R 1B ) 2 , —OC(═O)R 1B , —OC(═O)NHC(═O)R 1B , —OC(═O)NHSO 2 R 1B , —OSO 2 R 1B , or an aliphatic heteroaliphatic, aryl or heteroaryl moiety, or wherein R 1  and R 2  taken together are an alicyclic or heterocyclic moiety, or together are 
       
       
         
           
           
               
               
           
         
         wherein each occurrence of R 1A  and R 1B  is independently hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —C(═O)R 1C , or —C(═O)NR 1C R 1D ; wherein each occurrence of R 1C  and R 1D  is independently hydrogen, hydroxyl, or an aliphatic, heteroaliphatic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and R 1E  is hydrogen, an aliphatic, alicyclic, heteroaliphatic, heterocyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, —CN, —OR 1C , —NR 1C R 1D  or —SO 2 R 1C ; 
         R 3  is —C(═O)OR 3A , —C(═O)H, —CH 2 OR 3A , —CH 2 C(═O)-alkyl, —C(═O)NH(R 3A ), —CH 2 X 0 ; wherein each occurrence of R 3A  is independently hydrogen, a protecting group, an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl, alkylheteroaryl, heteroalkylaryl heteroalkylheteroaryl moiety, or pharmaceutically acceptable salt or ester, or R 3A , taken together with R 1  and R 2 , forms a heterocyclic moiety; wherein X 0  is a halogen selected from F, Br or I; 
         wherein R 4A  and R 4B  are independently a halogen selected from F, Cl, Br or I; and R B1 , R B2  and R E  are independently hydrogen or substituted or unsubstituted lower alkyl; 
         AR 1  is a monocyclic or polycyclic aryl, heteroaryl, alkylaryl, alkylheteroaryl, alicyclic or heterocyclic moiety; and, 
         L is absent or is V—W—X—Y—Z, wherein each occurrence of V, W, X, Y and Z is independently absent, C═O, NR L1 , —O—, —C(R L1 )═, ═C(R L1 )—, —C(R L1 )(R L2 ), C(═N—OR L1 ), C(═NR L1 ), —N═, S(O) 0-2 ; a substituted or unsubstituted C 1-6  alkenylidene or C 2-6  alkenylidine chain wherein up to two non-adjacent methylene units are independently optionally replaced by —C(═O)—, —CO 2 —, —C(═O)C(═O)—, —C(C═O)NR L3 —, —OC(═O)—, —OC(═O)NR L3 —, —NR L3 NR L4 —, —NR L3 NR L4 C(═O)—, —NR L3 C(═O)—, NR L3 CO 2 —, NR L3 C(═O)NR L4 —, —S(═O)—, —SO 2 —, —NR L3 SO 2 —, —SO 2 NR L3 , —NR L3 SO 2 NR L4 , —O—, —S—, or —NR L3 —; wherein each occurrence of R L3  and R L4  is independently hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or acyl; or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety; and each occurrence of R L1  and R L2  is independently hydrogen, hydroxyl, protected hydroxyl, amino, protected amino, thio, protected thio, halogen, cyano, isocyanate, carboxy, carboxyalkyl, formyl, formyloxy, azido, nitro, ureido, thioureido, thiocyanato, alkoxy, aryloxy, mercapto, sulfonamido, benzamido, tosyl, or an aliphatic, alicyclic, heteroaliphatic, heteroalicyclic, aryl, heteroaryl, alkylaryl or alkylheteroaryl moiety, or wherein one or more occurrences of R L1  and R L2 , taken together, or taken together with one of V, W, X, Y or Z form an alicyclic or heterocyclic moiety or form an aryl or heteroaryl moiety. 
       
     
     
         25 . The method of  claim 24 , wherein following administration, the LFA-1 antagonist is present in a therapeutically effective concentration within about 1 mm of an epithelial surface to which the formulation is applied and is present in blood plasma below a therapeutically effective level, within about 4 hours after administration. 
     
     
         26 . The method of  claim 24 , wherein following administration, the LFA-1 antagonist is present in a therapeutically effective concentration within about 1 mm of an epithelial surface to which the formulation is applied and is present in blood plasma below a therapeutically effective level, within about 4 hours following administration. 
     
     
         27 . The method of  claim 24 , wherein the LFA-1 antagonist has a local tissue concentration of greater than about 10 nM within about 4 hours following administration. 
     
     
         28 . The method of  claim 24 , wherein the LFA-1 antagonist has a local tissue concentration of greater than about 1 μM and a systemic concentration as measured in plasma of less than about 100 nM, within about 4 hours following administration. 
     
     
         29 . The method of  claim 27 , wherein the local tissue concentration of the LFA-1 antagonist is maintained at greater than about 10 nM for at least about 8 hours following administration. 
     
     
         30 . The method of  claim 24 , wherein the LFA-1 antagonist is a directly competitive antagonist. 
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 24 , wherein the LFA-1 antagonist has one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         33 . The method of  claim 24  wherein the LFA-1 antagonist is a compound having the following formula: 
       
         
           
           
               
               
           
         
       
     
     
         34 . The method of  claim 33  wherein the LFA-1 antagonist is any of Form A, Form B, Form C, Form D, Form E, an amorphous form, or a combination thereof of the compound of  claim 33 . 
     
     
         35 . The method of  claim 34  wherein the LFA-1 antagonist is form A of the compound of  claim 33 . 
     
     
         36 . The method of  claim 24 , wherein the LFA-1 antagonist inhibits T-cell attachment to ICAM-1 by about 50% or more at a concentration of about 100 nM. 
     
     
         37 . The method of  claim 24 , wherein the formulation is topically applied to skin, eyes, mouth, nose, vaginal mucosa or anal mucosa. 
     
     
         38 . The method of  claim 24 , wherein the formulation is in the form of a gel, cream, lotion, solution, suspension, emulsion, ointment, powder, crystalline forms, spray, foam, salve, paste, plaster, paint, slow release nanoparticle, slow release microparticle, or bioadhesive. 
     
     
         39 . The method of  claim 24 , wherein the formulation further comprises at least one additional therapeutic agent. 
     
     
         40 . The method of  claim 39 , wherein the additional therapeutic agent is an antioxidant, antiinflammatory agent, antimicrobial agent, antiangiogenic agent, anti-apoptotic agent, vascular endothelial growth factor inhibitor or antiviral agent. 
     
     
         41 . The method of  claim 24 , wherein the formulation is administered in a dose from about 0.01 to about 5 mg. 
     
     
         42 . The method of  claim 24 , wherein the inflammatory or immune disorder is intraocular inflammation, periocular inflammation, ocular surface inflammation, Keratoconjunctivitis, keratoconjunctivitis sicca (KCS, aka Dry Eye), KCS in patients with Sjogren's syndrome, age related macular degeneration (AMD), allergic conjunctivitis, uveitis, inflammation of the eye from contact lens wear, inflammation of the cornea from contact lens wear, inflammation of the periocular tissue from contact lens wear, inflammation of the eye following surgery, intraocular inflammation, retinitis, edema, retinopathy, corneal inflammation, Graves' disease (Basedow disease) or Graves ophthalmopathy. 
     
     
         43 . The method of  claim 24 , wherein the inflammatory or immune disorder is psoriasis, irritant contact dermatitis, eczematous dermatitis, seborrhoeic dermatitis, cutaneous manifestations of immunologically-mediated disorders, alopecia, alopecia areata, adult respiratory distress syndrome, pulmonary fibrosis, scleredoma, scar formation, chronic obstructive pulmonary disease (COPD), atopic dermatitis, inflammation from kidney transplant, asthma, hidradentis supporativa, rheumatoid arthritis, psoriatic arthritis, Sjogren's Syndrome, uveitis, Graft vs. Host disease (GVHD), Oral Lichen Planus, arthralgia or Islet Cell Transplant inflammation.